The problem of obtaining selectivity in nurturing, or more frequently destroying, certain biological tissues and organisms is well recognized, and mostly unsolved. Examples are legion. One would like to be able to exterminate garden pests without poisoning the cat. One would like to rid the lawn of weeds without killing the grass. It would be desirable to destroy malignant tissue without incapacitating the host's own cells.
Various approaches have been made to this problem. In the most commonly used, an empirical study to determine materials which happen to be more effective with the desired target has resulted in a variety of agents which are inherently selective. While having yielded successful results in some cases, the general method of trial and error does not yield a directed procedure with a high probability of success. At a somewhat more sophisticated level, known differences in metabolism between various target cells can be used to postulate structures for agents which may exhibit differential activity. For example, many antitumor agents are inhibitors of DNA synthesis which are directed to undermining the rapid replication characteristic of tumor cells. This is an example of functional selectivity, which resides in a difference between target and nontarget in sensitivity to a particular substance. Perhaps the most recent approach has been to utilize specific cellular receptors as means to bind particular drugs or toxins to a target cell. This may be regarded as "passive" selectivity, which resides in a difference in the attractiveness of the target environment to a material. In applying this concept, for example, it has been hoped that immunotoxins will become successful as tools in cancer therapy, and that radioactive isotopes bound to, for example, specific antibodies can be targeted to their desired locations.
In the approach described in the present invention a reaction which is at least bimolecular is selectively conducted in the microenvironment of the targeted tissue. Because the assembly of an active reagent from at least two portions (which may or may not be identical) inherently amplifies the selectivity of a microenvironment characterizing the target, quantitative as well as qualitative differences in such microenvironments can be employed. The microenvironment may influence the reaction by concentrating one or more of the components of the reaction at the desired location, by activating one or more of these components, by stabilizing (or not destabilizing) one of the components or the product, or by affecting the rate constant of the reaction which results in assembly of the active product. These are all passive selectivity factors.
It has, of course, been proposed to take advantage of passive selectivity factors directly by targeting specific cells or tissues for the active drug or label in the practice for using immunotoxins or other immunoconjugates as mentioned above. In addition, it has been suggested that passive selectivity factors relating to differential metabolism of pro-drugs in normal and target tissues be employed to effect a differential concentration of the pro-drug in the target tissue, whereupon an activating substance is supplied to release from the pro-drug the active, usually toxic, compound. Walker, E. H. in an article entitled "Chemically Triggered Time-Delay Activation Chemotherapy for the Treatment of Cancer" in Perspectives in Biology and Medicine (Spring 1980) pp. 424-438, suggests this concept, designated "triggered time-delay toxin activation", or "TDTA" in connection with tumor therapy. This approach, however, does not envision assembly of the active compound, but rather the release of the active moiety from the pro-drug. Specific suggestions for such release are, in fact, limited to enzymatic release of functional portions of the pro-drug using later-administered enzyme preparations.